Anopheline mosquitoes constitute the primary vectors of malaria. Recent developments in mosquito research, that were highlighted by the publication of a draft genome sequence of the primary African malaria vector Anopheles gambiae, provide exciting opportunities to greatly enhance our understanding of mosquito genetics, behavior, and physiology. New insights in mosquito biology will undoubtedly facilitate the development of novel strategies to combat malaria and other mosquito-borne diseases. The basic concept underlying this proposal is to combine comparative inquiry with modern genomic technology to help realize the promise of the An. gambiae genome project. The long-term objective of this exploratory R21 project is to develop an efficient method of multi-species comparisons of targeted genomic regions to illuminate what makes a mosquito a competent vector for pathogens, an anthropophilic biter, and an adaptive survivor under different ecological conditions. Here we will target genomic regions that contain odorant receptor (GPRor) genes or gene clusters because of their potential roles in host-seeking behavior of An. gambiae. We will pursue three Specific Aims: 1) Sequence 12 randomly picked BAC clones from An. stephensi to obtain baseline information on the relative genomic organization and evolutionary divergence between An. stephensi and An. gambiae. 2) Target 6 regions that contain GPRor genes or gene clusters for pair-wise comparisons between An. stephensi and An. gambiae to examine the evolutionary divergence, conserved regulatory elements, and expansions/loss/rearrangements of these genes. 3) Further target 2 GPRor regions for multi-species comparisons to efficiently identify potential regulatory elements, detect local gene expansions/loss/rearrangements, and examine possible correlations between these genetic changes and biological adaptations.